Compositions of n-(methylethaylaminocarbonyl)-4-(-3-methylphenylamino)-3-pyridylsulfonamide and cyclic oligosacccharides

ABSTRACT

The invention relates to compositions of N-(1-methylethylaminocarbonyl)4(3-methylphenylamino)-3-pyridylsul-fonamide and cyclic oligosaccharides with increased release, to methods for their preparation, to pharmaceutical froms containing them as well as to their use.

[0001] The present invention relates to compositions ofN-(1-methylethylaminocarbonyl)4-(3-methylphenylamino)-3-pyridylsulfonamide(further in the text referred to by its generic name “torasemide”) andcyclic oligosaccharides with increased release, to methods for theirpreparation, to pharmaceutical forms containing them as well as to theiruse.

[0002] Torasemide is a new potent diuretic in the class of the so-called“loop diuretics”, which is described in the Example 71 of DE patent 2515 025. Structurally, it entirely differs from diuretics of the sameclass such as furosemide, bumetanide and azosemide. In addition todiuretic properties it also possesses antihypertensive properties.

[0003] As a diuretic of Henle's loop it is interesting as an agent forpreventing heart damages or heart tissue damages caused by metabolic orionic abnormalities associated with ischemia, in the treatment ofthrombosis, angina pectoris, asthma, hypertension, nephroedema,pulmonary edema, primary and secondary aldosteronism, Batter's syndrome,tumours, glaucoma, decrease of intraocular pressure, acute or chronicbronchitis, in the treatment of cerebral edema caused by trauma,ischemia, concussion of the brain, metastases or epileptic attacks andin the treatment of nasal infections caused by allergens.

[0004] It is well known that torasemide can exist in four crystalmodifications: polymorph I [Acta Cryst. B34, (1978) 1304-1310],polymorph II (Acta Cryst. B34, (1978) 2659-2662], polymorph III (PCT/WO00/20395) and polymorph V (HR Patent Application No. P 20000328A), andin one amorphous modification (HR Patent Application No. P 20000162A).

[0005] Modifications of torasemide (polymorphs I-V) are very hydrophobicand practically insoluble in water. Very poor water-solubility andwettability of torasemide represents a problem in the preparation ofpharmaceutical preparations with good dissolution and uniformbioavailability.

[0006] The problem of increasing the dissolution rate of activesubstances that are poorly soluble in water covers many areas rangingfrom phytopharmaceuticals to pesticides and, in general, all those areaswhere bioactive substances are used.

[0007] The dissolution rate is determined by physical-chemicalcharacteristics of the active substance and particularly by itssolubility in water. Thus, the dissolution rate of an active substanceis the limiting factor in the absorption process and in the therapeuticactivity of the substance. Additionally, disintegration products of theactive substance formed in pharmaceutical preparations may also causedifferent side effects. Therefore an increased solubility and stabilityachieved by the preparation of a suitable formulation results in anincreased efficiency of the active substance. In pharmaceuticalindustry, the increase of the dissolution rate and of the stability ofpoorly soluble active substances has been solved by various methods e.g.by micronization, by preparing amorphs, clathrates, by chemicalmodifications, by pH adjustment and very often by preparing solidcompositions of the active substance and physiologically suitableadditives making possible the desired physical-chemical transformationof the active substance i.e. improving the dissolution rate and thewettability of the active substance. As physiologically suitableadditives there are usually used e.g. polyvinylpyrrolidone,carboxymethylcellulose, hydroxypropyl-cellulose and, with increasingfrequency, cyclodextrins, commercially available cyclic oligosaccharidesconsisting of 6, 7 and 8 linked glucopyranose units (α-,β- andγ-cyclodextins and their derivatives).

[0008] Solid compositions active substance/physiologically suitableadditive can be prepared by blending, milling, precipitation,evaporation, lyophilization, spray-drying and melting.

[0009] Properties of cyclodextrins are well known and have beendescribed in detail in reviews in periodicals [Szejtli J., CyclodextrinTechnology (1988) Kluwer Academic Publishers, Dordrecht; Szejtli J.,Cyclodextrins in drug formulations: Part I, Pharm. Techn. Int. 3 (1991)15-22; Szejtli J., Cyclodextrins in drug formulations: Part II, Pharm.Techn. Int. 3 (3) (1991) 16-24; T. Loftson, Pharmaceutical Applicationof β-Cyclodextrin, Pharm. Techn. Eur. 11 (1999) 20; W. Saenger,Cyclodextrin Inclusion Compounds in Research and Industry, Angew. Chem.Int. Ed Engl. 19 (1980) 344].

[0010] Cyclodextrins are characterized by the shape of their molecule inthe form of a cylinder. Inside the cylinder there is an intramolecularcavity which is hydrophobic, whereas the outer side is hydrophilic. Thehydrophobic character of the intramolecular cavity enables othermolecules or parts of molecules known as “guest” molecules to penetrateinto the host molecule thereby forming inclusion complexes.

[0011] An inclusion complex can be stabilized by numerous forcesincluding also Van der Waals' attracting forces and hydrogen bonds.Inclusion complexing of the corresponding “guest” molecule withcyclodextrins may result in numerous physical-chemical changes in theproperties of the “guest” molecule. The melting point is changed, the IRspectrum and X-ray powder pattern of the complex are relativelydifferent from those of the pure “guest” molecule or of a simple (notcomplexed) mixture of the “host” molecule and the “guest” molecule. Bymeans of cyclodextrin inclusion complex, water-insoluble “guest”molecules become more soluble. In many cases chemically unstablecompounds are stabilized by inclusion complexing. The said changes inphysical-chemical properties of the “guest” molecule resulting frominclusion complexing with cyclodextrins, represent a proof that thecyclodextrin inclusion complex represent an unique form of the solidstate of a “guest” molecule.

[0012] Though by the preparation of the solid compositions activesubstance/physiologically suitable additive an increased dissolutionrate has been noticed in a large number of poorly solublepharmaceutically active substances, this cannot be accepted as a rule.Namely, for each active substance and physiologically suitable additiveit has to be established which preparation method, physiologicallysuitable additive and molar ratio active substance/physiologicallysuitable additive, solvent, time, temperature of the preparation etc.will give a solid composition making possible the desired dissolutionrate of the active substance.

[0013] Solid compositions of cyclodextrin with various pharmaceuticallyinteresting active substances have been known from patents as well asfrom the literature and just a few examples are cited here.

[0014] Thus, M. I. La Rotonda et al. compared solid compositions of thenon-steroid antiinflammatory drug nimesulide and β-cyclodextrin (molarratio 1:1) prepared by physical blending, evaporation, lyophilization,spray-drying and kneading and reported that the dissolution rate dependson physical-chemical properties of each solid composition. In comparisonto nimesulide alone, the dissolution of nimesulide from solidcompositions was significantly accelerated and the solid compositionsobtained by lyophilization and spray-drying showed to be the forms withthe fastest dissolution of nimesulide [S.T.P. Pharma Sci. 10 (2000)157].

[0015] P. R. Vavia et al. also compared solid compositions of nimesulidewith β-cyclodextrin and HP-β-cyclodextrin in a molar ratio 1:1 (physicalmixtures and lyophilizates). As stated by the authors, in contrast tophysical mixtures, the inclusion complexes prepared by lyophihizationincreased the dissolution of nimesulide, and particularly by theinclusion complex niinesulide/HP-β-cyclodextins a significantly higherdissolution was achieved [Drug Develop. Ind. Pharm. 25 (1999) 543].

[0016] J. R. Mayano et al. prepared, by physical mixing, spray-dryingand kneading, solid compositions of the drug oxazepam with,β-cyclodextrin in molar ratios 1:1 and 1:2, and all solid compositionsaccelerated the dissolution of oxazepam in comparison to oxazepam alone.In the case of physical mixtures, both molar ratios of oxazepam toβ-cyclodextrin showed an equal influence on the dissolution of oxazepamwhereas the solid compositions prepared by kneading and spray-dryingwith the molar ratio 1:2 considerably accelerated the dissolution ofoxazepam in comparison to those with the molar ratio 1:1 [Int. J. Pharm.114 (1995) 95].

[0017] Further, M. Guyot et al. prepared physical mixtures and inclusioncomplexes of the drug norfloxacin with β-cyclodextrin andHP-β-cyclodextrin in molar ratios 1:1 and 1:2. Physical mixtures as wellas inclusion complexes significantly increased the dissolution incomparison to norfloxacin alone. No influence of molar ratios ondissolution was noticed [Int. J. Pharm. 123 (1995) 53]

[0018] Besides, M. Pedersen et al. stated that physical mixtures of theantimicotic miconazole and β-cyclodextrin with the molar ratio 1:2 showa faster dissolution in comparison to the inclusion complex withβ-cyclodextrin [Drug. Develop. Ind. Pharm. 25 (1999) 1241].

[0019] In U.S. pat. No. 5,849,329 the authors protected a process forpreparing pharmaceutical compositions with controlled dissolution,prepared by grinding or dry-mixing active substances also with, interalia, α-, β-, γ- and HP-β-cyclodextrins and their derivatives. As activesubstances there were cited naftazone, terfenadine, carbamazepine,glicazide, glibenclamide, bifonazole as well as nifedipine, diazepam andketoprofen.

[0020] In U.S. pat. No. 5,449,521 the authors protected pharmaceuticalcompositions containing griseofulvin, piroxicam, diacerein, diltiazem,megestrol acetate, nifedipine, nicergoline, ketoprofen, naproxen,diclofenac, ibuprofen, lorazepam, oxazepam as an active substance and,inter alia, cross-linked polymeric cyclodextin. The cited pharmaceuticalcompositions were prepared by grinding the active substance and asuitable additive in mills saturated with the vapours of a solvent or ofa mixture of solvents.

[0021] Besides, in U.S. pat. No. 5,010,064 the authors protected aninclusion complex of dipyrimidole and β-cyclodextrin (molar ratio from1:1 to 1:12), whereas in U.S. pat. No. 5,019,563 a complex of ibuprofensodium salt and β-cyclodextrin (molar ratio 1:0.2 to 1:0.75) wasprotected.

[0022] Further, in U.S. pat. No. 5,674,854 the authors described andprotected the preparation and an inclusion complex of pharmaceuticallysuitable salts of diclofenac and β-cyclodextrin (molar ratio 1:1) and inU.S. pat. No. 5,744,165 the authors protected inclusion complexes ofalkali metal salts and earth alkali metal salts of nimesulide with α-,β- and γ-cyclodextrins and derivatives thereof.

[0023] In the patent publication WO 93/00097 the authors claimed stablepharmaceutical preparations containing torasemide or its salts andadditives such as hydroxy-propylcellulose, polyvinylpyrrolidone,sodium-croscarmellose, cros-povidone, calcium-carboxymethylcellulose,lower substituted hydroxypropylcellulose, modified starch etc.Cyclodextrins were not cited therein.

[0024] In our further research in the field of torasemide we havesuprisingly found that physical mixtures of modifications I-V oftorasemide with cyclodextrins or cyclodextrin derivatives distinguishthemselves by a faster dissolution of torasemide. Additionally, it hasbeen suprisingly found that inclusion complexes of the modifications I-Vof torasemide with cyclodextrins or cyclodextrin derivatives distinguishthemselves by a faster dissolution of torasemide.

[0025] Firstly, the present invention relates to physiologicallysuitable physical mixtures of modifications I, II, III, IV or V oftorasemide with cyclodextrins or cyclodextrin derivatives or to anymixture of modifications I, II, III, IV and V of torasemide andcyclodextrins or cyclodextrin derivatives.

[0026] Cyclodextrins contained in the physical mixtures are α-, β- andγ-cyclodextrins and their derivatives. Suitable derivatives of α-, β-and γ-cyclodextrins are their ethers and mixed ethers having one or moregroups of anhydroglucose parts of cyclodextrin substituted withC₁₋₆alkyl, preferably methyl, ethyl or isopropyl; hydroxyC₁₋₆alkyl,preferably hydroxyethyl or hydroxypropyl or hydroxybutyl;carboxyC₁₋₆alkyl, preferably carboxymethyl or carboxyethyl;C₁₋₆alkylcarbonyl, preferably acetyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl orcarboxy-C₁₋₆alkoxy-C₁₋₆alkyl, preferably carboxy-methoxypropyl orcarboxyethoxypropyl; C₁₋₆alkoxycarbonyloxyC₁₋₆alkyl, preferably2-acetyloxypropyl. Particularly important cyclodextrins or theirderivatives are α-, β-and γ-cyclodextrins,2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclo-dextrin,2-hydroxypropyl-γ-cyclodextin, 2-hydroxyethyl-β-cyclodextrin,2-hydroxy-ethyl-γ-cyclodextrin, 2,6-dimethyl-β-cyclodextrin and(2-carboxymethoxy)-propyl-β-cyclodextrin.

[0027] In general, in physical mixtures of the present invention themolar ratio of the modifications I-V of torasemide to cyclodextrins orcyclodextrin derivatives may range from 1:0.1 to 1:5.

[0028] Further, the present invention relates to a method for thepreparation of the aforementioned physical mixtures of modifications I-Vof torasemide and cyclodextrins or cyclodextrin derivatives. Inpractice, the method can be carried out according to the followingmethod:

[0029] A modification I, II, III, IV or V of torasemide andcyclodextrins or cyclodextrin derivatives or any mixture ofmodifications I, II, III, IV and V of torasemide and cyclodextrins orcyclodextrin derivatives are combined in a specific molar ratio,homogenized in a mortar or mixers commonly used in pharmaceuticalindustry at a temperature and over a time period required for obtaininga mixture with the desired dissolution rate of torasemide.

[0030] In accordance with the first object of the invention, the presentinvention also relates to physiologically suitable inclusion complexesof modifications I, II, III, IV or V of torasemide with cyclodextrins orcyclodextrin derivatives or of any mixture of modifications I, II, III,IV and V of torasemide and cyclodextrins or cyclodextrin derivatives .

[0031] Cyclodextrins contained in inclusion complexes are α-, β- andγ-cyclodextrins or their derivatives. Suitable derivatives of α-, β- andγ-cyclodextrins are their ethers or mixed ethers having one or moregroups of anhydroglucose parts of cyclodextin substitued with C₁₋₆alkyl,preferably methyl, ethyl or isopropyl; hydroxyC₁₋₆alkyl, preferablyhydroxyethyl or hydroxypropyl or hydroxybutyl; carboxyC₁₋₆alkyl,preferably carboxymethyl or carboxyethyl; C₁₋₆alkylcarbonyl, preferablyacetyl; C₁₋₆alkoxy-carbonyl C₁₋₆alkyl or carboxy-C₁₋₆alkoxy-C₁₋₆alkyl,preferably carboxymethoxypropyl or carboxyethoxypropyl;C₁₋₆alkoxycarbonyloxyC₁₋₆alkyl, preferably 2-acetyloxy-propyl.Particularly important cyclodextrins or their derivatives are α-, β- andγ-cyclodextrins, 2-hydroxypropyl-α-cyclodextrin,2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin,2-hydroxyethyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclodextrin,2,6-dimethyl-β-cyclodextrin and (2-carboxymethoxy)propyl-β-cyclodextrin.

[0032] In general, in inclusion complexes of the present invention themolar ratio of modifications I-V of torasemide to cyclodextrins orcyclodextrin derivatives may range from 1:0 to 1:5.

[0033] Further, the present invention relates to a method for thepreparation of the aforementioned inclusion complexes of modificationsI-V of torasemide and cyclodextrins or cyclodextrin derivatives. Inpractice the method can be carried out according to the followingmethod:

[0034] A modification I, II, III, IV or V of torasemide or any mixtureof modifications I, II, III, IV and V of torasemide is added to anaqueous solution of cyclodextrins or cyclodextrin derivatives and, withor without the addition of an aqueous ammonia solution, it is stirred ata temperature and over a time period required for the formation of theinclusion complex. After the inclusion complex has been formed, water isremoved by lyophilization, spray-drying, vacuum evaporation at lowertemperatures or by any other method known in the pharmaceutical art.

[0035] The physical mixtures of modifications I-V of torasemide andcyclodextrins or cyclodextrin derivatives as well as the inclusioncomplexes of modifications I-V of torasemide and cyclodextrins orcyclodextrin derivatives prepared according to the methods of thepresent invention can, as a suitable torasemide form, be used as adiuretic or as an agent for preventing heart damages or heart tissuedamages caused by metabolic or ionic abnormalities associated withischemia, in the treatment of thrombosis, angina pectoris, asthma,hypertension, nephroedema, pulmonary edema, primary and secondaryaldosteronism, Batter's syndrome, tumours, glaucoma, decrease ofintraocular pressure, acute or chronic bronchitis, in the treatment ofcerebral edema caused by trauma, ischemia, concussion of the brain,metastases or epileptic attacks and in the treatment of nasal infectionscaused by allergens.

[0036] The present invention also relates to pharmaceutical forms suchas tablets, capsules, injections or sprays containing physical mixturesor inclusion complexes of modifications I, II, III, IV or V oftorasemide and cyclodextrins or cyclodextrin derivatives or of anymixture of modifications I, II, III, IV and V of torasemide withcyclodextrins or cyclodextrin derivatives as the active ingredient,without any additives or in combination with one or morepharmaceutically acceptable additives such as sugar, starch, starchderivatives, cellulose, cellulose derivatives, mould release agents andantiadhesive agents and optionally agents for flowability regulation.

[0037]FIG. 1 represents the DSC curve of β-cyclodextrin.

[0038]FIG. 2 represents the DSC curve of the modification I oftorasermide.

[0039]FIG. 3 represents the DSC curve of the physical mixture of themodification I of torasemide and β-cyclodextrin (molar ratio 1:1).

[0040]FIG. 4 represents the DSC curve of the inclusion complex of themodification I of torasemide and β-cyclodextrin (molar ratio 1:1).

[0041]FIG. 5 represents the IR spectrum of β-cyclodextrin recorded inKBr.

[0042]FIG. 6 represents the IR spectrum of the modification I oftorasemide recorded in KBr.

[0043]FIG. 7 represents the IR spectrum of the physical mixture of themodification I of torasemide and β-cyclodextrin (molar ratio 1:1)recorded in KBr.

[0044]FIG. 8 represents the IR spectrum of the inclusion complex of themodification I of torasemide and β-cyclodextrin (molar ratio 1:1)recorded in KBr.

[0045]FIG. 9 represents the X-ray powder pattern of β-cyclodextrin.

[0046]FIG. 10 represents the X-ray powder pattern of the modification Iof torasemide. FIG. 11 represents the X-ray powder pattern of thephysical mixture of the modification I of torasemide and β-cyclodextrin(molar ratio 1:1).

[0047]FIG. 12 represents the X-ray powder pattern of the inclusioncomplex of the modification I of torasemide and β-cyclodextrin (molarratio 1:1).

[0048] The present invention is illustrated but in no way limited by thefollowing examples.

EXAMPLE 1

[0049] The modification I of torasemide according to PCT/WO 00/20395(0.50 g) and an equimolar amount of β-cyclodextrin were homogenized in amixer for 24 hours.

[0050] Differential scanning calorimetry (DSC) curve represented in FIG.3 comprises exothermic peaks of the modification I of torasemide andβ-cyclodextrin. The DSC analysis was performed on the apparatusPerkin-Elmer, model DSC7 at a heating rate of 25° C./min.

[0051] The IR spectrum represented in FIG. 7 comprises characteristicpeaks of the modification I of torasemide and β-cyclodextrin. The IRspectrum was recorded on the IR spectrophotometer Nicolet, model Magna760 in the range from 4000 to 600 cm⁻¹.

[0052] The representative X-ray powder pattern is represented in FIG. 11and was recorded on the diffractometer PHILIPS, model PW 3710 in therange 2θ=5-40° using CuKα rays =1.541 Å. The recording step was 0.029°and the recording time was 1 s per step.

EXAMPLE 2

[0053] The physical mixture of the modification I of torasemide andβ-cyclodextrin prepared according to the Example 1 of the presentinvention was subjected to testing the release of the active substancein water at the temperature of 37° C. (USP 24) and the results are shownin Table 1. TABLE 1 Release of torasemide from the physical mixture ofthe modification I of torasemide and β-cyclodextrin (molar ratio 1:1) inwater (USP 24) (37° C., 50 rpm, 1000 ml) Time Released torasemide (%)(min) Modification I of torasemide Physical mixture 0 0 0 15 0.7 32.2 3020.3 57.1 45 38.5 70.2 60 51.8 80.6 90 68.5 89.1 120 78.7 93.8

EXAMPLE 3

[0054] β-Cyclodextrin (1.81 g) was dissolved in 50 ml of demineralisedwater and 10 drops of an aqueous ammonia solution were added.Subsequently, an equimolar amount of the modification I of torasemideprepared according to PCT/WO 00/20395 was added to the solution, it wasvigorously stirred for 24 hours and then filtered and water was removedby lyophilization.

[0055] The formation of the inclusion complex of torasemide andβ-cyclodextrin was proven by the data obtained by differential scanningcalorimetry, IR analysis and X-ray powder pattern.

[0056] The differential scanning calorimetry (DSC) curve represented inFIG. 4 does not comprise strong peaks characteristic of the modificationI of torasemide and of ,β-cyclodextrin.

[0057] The IR spectrum represented in FIG. 8 strongly differs from theIR spectrum of the modification I of torasemide and from the IR spectrumof β-cyclodextrin represented in FIGS. 5 and 6.

[0058] The X-ray powder pattern represented in FIG. 12 strongly differsfrom the X-ray powder pattern of the modification I of torasemide andthe X-ray powder pattern of β-cyclodextrin represented in FIGS. 10 and11.

EXAMPLE 4

[0059] β-Cyclodextrin (0.28 g) was dissolved in 50 ml of demineralisedwater, the solution was heated to 80° C. under vigorous stirring, it wasstirred for 60 minutes and then an equimolar amount of the modificationI of torasemide prepared according to PCT/WO 00/20395 was added over 90minutes. Subsequently, the hot solution was filtered, cooled to roomtemperature, whereupon water was removed by lyophilization.

[0060] The IR spectrum of the thus obtained sample was identical to theIR spectrum of the sample prepared according to the Example 3 of thepresent invention.

EXAMPLE 5

[0061] The inclusion complex of the modification I of torasemide andβ-cyclodextrin to the Example 3 of the present invention was subjectedto testing the release of the active substance in water at thetemperature of 37° C. (USP 24) and the results are shown in Table 2.TABLE 2 Release of torasemide from the inclusion complex of themodification I of torasemide and β-cyclodextrin (molar ratio 1:1) inwater (USP 24) (37° C., 50 rpm, 1000 ml) Time Released torasemide (%)(min) Modification I of torasemide Inclusion complex 0 0 0 15 0.7 95.830 20.3 98.2 45 38.5 97.9 60 51.8 98.3 90 68.5 98.8 120 78.7 98.5

1. Physical mixtures, characterized in that they comprise torasemide andcyclodextrins or cyclodextrin derivatives.
 2. Physical mixturesaccording to claim 1, characterized in that torasemide is selected froma group consisting of modifications I, II, III, IV and V or any mixturethereof.
 3. Physical mixtures according to claim 1, characterized inthat cyclodextrin is selected from a group consisting of α-, β- andγ-cyclodextrin.
 4. Physical mixtures according to claim 1, characterizedin that cyclodextin derivatives are selected from the group of ethers ormixed ethers of α-, β- and γ-cyclodextrins having one or more groups ofanhydroglucose parts of cyclodextrin substituted with C₁₋₆alkyl,preferably methyl, ethyl or isopropyl; hydroxyC₁₋₆alkyl, preferablyhydroxyethyl or hydroxypropyl or hydroxybutyl; carboxyC₁₋₆alkyl,preferably carboxymethyl or carboxyethyl; C₁₋₆alkylcarbonyl, preferablyacetyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl or carboxy-C₁₋₆alkoxy-C₁₋₆alkyl,preferably carboxymethoxypropyl or carboxyethoxypropyl;C₁₋₆alkoxy-carbonyloxyC₁₋₆alkyl, preferably 2-acetyloxypropyl. 5.Physical mixtures according to claim 1, characterized in thatcyclodextrin derivatives are selected from the group of2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin,2-hydroxypropyl-γ-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin,2-hydroxyethyl-γ-cyclodextrin, 2,6-dimethyl-β-cyclodextrin and(2-carboxymethoxy)-propyl-β-cyclodextrin.
 6. Physical mixtures accordingto claim 1, characterized in that torasemide and cyclodextrins orcyclodextrin derivatives are in a molar ratio from 1:0.1 to 1:5.
 7. Amethod for the preparation of physical mixtures according to claim 1,characterized in that torasemide and cyclodextrins or cyclodextrinderivatives are homogenized.
 8. A method for the preparation of physicalmixtures according to claim 7, characterized in that the saidhomogenization is carried but in a mortar or in mixers.
 9. A method forthe preparation of physical mixtures according to claim 7, characterizedin that the said mixing is carried out at temperatures from 10° C. to100° C.
 10. A method for the preparation of physical mixtures accordingto claim 7, characterized in that the said mixing is carried out from0.1 hour to 24 hours.
 11. Physical mixtures according to claim 1,characterized in that they are used as a diuretic and as an agent forpreventing heart damages or heart tissue damages caused by metabolic orionic abnormalities associated with ischemia, in the treatment ofthrombosis, angina pectoris, asthma, hypertension; nephroedema,pulmonary edema, primary and secondary aldosteronism, Batter's syndrome,tumours, glaucoma, decrease of intraocular pressure, acute or chronicbronchitis, in the treatment of cerebral edema caused by trauma,ischemia, concussion of the brain, metastases or epileptic attacks andin the treatment of nasal infections caused by allergens.
 12. Apharmaceutical form, characterized in that it comprises physicalmixtures according to claim 1 as the active substance in combinationwith one or more pharmaceutically acceptable additives such as sugar,starch, starch derivatives, cellulose, cellulose derivatives, mouldrelease agents and antiadhesive agents and optionally agents forflowability regulation.
 13. A pharmaceutical form according to claim 12,characterized in that it is a tablet, a capsule, an injection or aspray.
 14. Inclusion complexes characterized in that they comprisetorasemide and cyclodextrins or cyclodextrin derivatives.
 15. Inclusioncomplexes according to claim 14, characterized in that cyclodextrin isselected from a group consisting of α-, β- and γ-cyclodextrin. 16.Inclusion complexes according to claim 14, characterized in that thecyclodextrin derivatives are selected from a group of ethers or mixedethers of α-, β- and γ-cyclodextrins having one or more groups ofanhydroglucose parts of cyclodextrin substituted with C₁₋₆allyl,preferably methyl, ethyl or isopropyl; hydroxyC₁₋₆alkyl, preferablyhydroxyethyl or hydroxypropyl or hydroxybutyl; carboxyC₁₋₆alkyl,preferably carboxymethyl or carboxyethyl; C₁₋₆alkylcarbonyl, preferablyacetyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl or carboxy-C₁₋₆alkoxy-C₁₋₆alkyl,preferably carboxymethoxypropyl or carboxyethoxypropyl;C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, preferably 2-acetyloxypropyl. 17.Inclusion complexes according to claim 14, characterized in thatcyclodextrin derivatives are selected from the group of2-hydroxypropyl-α-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin,2-hydroxypropyl-γ-cyclodextrin, 2-hydroxyethyl- β-cyclodextrin,2-hydroxyethyl-γ-cyclodextrin, 2,6-dimethyl-β-cyclodextrin and(2-carboxymethoxy)-propyl-β-cyclodextrin.
 18. Inclusion complexesaccording to claim 14, characterized in that torasemide andcyclodextrins or cyclodextrin derivatives are in a molar ratio from1:0.1 to 1:5.
 19. A method for the preparation of inclusion complexesaccording to claim 14, characterized in that torasemide andcyclodextrins or cyclodextrin derivatives are reacted in water with orwithout an aqueous solution of a base.
 20. A method for the preparationof inclusion complexes according to claim 19, characterized in that asthe aqueous solution of a base an aqueous ammonia solution is used. 21.A method for the preparation of inclusion complexes according to claim19, characterized in that it is carried out at temperatures from 10° C.to 100° C.
 22. A method for the preparation of inclusion complexesaccording to claim 19, characterized in that it is carried out for from0.1 hours to 7 days.
 23. A method for the preparation of inclusioncomplexes according to claim 19, characterized in that after formationof the said inclusion complex, the water and the base are removed bydrying.
 24. A method for the preparation of inclusion complexesaccording to claim 23, characterized in that the said drying is carriedout by lyophilization, spray-drying, vacuum evaporation or vacuumdrying.
 25. Inclusion complexes according to claim 14, characterized inthat they are used as a diuretic and as an agent for preventing heartdamages or heart tissue damages caused by metabolic or ionicabnormalities associated with ischemia, in the treatment of thrombosis,angina pectoris, asthma, hypertension, nephroedema, pulmonary edema,primary and secondary aldosteronism, Batter's syndrome, tumours,glaucoma, decrease of intraocular pressure, acute or chronic bronchitis,in the treatment of cerebral edema caused by trauma, ischemia,concussion of the brain, metastases or epileptic attacks and in thetreatment of nasal infections caused by allergens.
 26. A pharmaceuticalform, characterized in that it comprises inclusion complexes accordingto claim 14 as the active ingredient in combination with one or morepharmaceutically acceptable additives such as sugar, starch, starchderivatives, cellulose, cellulose derivatives, mould release agents andantiadhesive agents and optionally agents for flowability regulation.27. A pharmaceutical form according to claim 26, characterized in thatit is a tablet a capsule, an injection or a spray.